Tamoxifen Metabolism and CYP2D6 

Updated: Dec 07, 2018
  • Author: Maurie Markman, MD, MS; Chief Editor: Keith K Vaux, MD  more...
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Practice Essentials

Systemic tamoxifen has been the standard approach for reducing risk of recurrence in women with estrogen receptor (ER)–positive early-stage breast cancer for more than 40 years. Long-term data have demonstrated that the use of tamoxifen reduces recurrence and mortality by more than 30% in both premenopausal and postmenopausal women, regardless of the use of systemic chemotherapy. [1] Aromatase inhibitors (AIs), such as anastrozole (Arimidex) and exemestane (Aromasin), have been proven to be as effective as, or superior to, tamoxifen. AIs have been utilized as initial adjuvant therapy, as sequential therapy followed by 2-3 years of tamoxifen, or as an extended therapy following 4.5-6 years of tamoxifen. [2]

Tamoxifen is metabolized via CYP2D6 into endoxifen (4-OH-N-desmethyl-tamoxifen), its primary active metabolite. Multiple investigations have identified genetic variants of CYP2D6 that can affect its activity, which in turn affects the metabolism of tamoxifen. The proficiency with which CYP2D6 metabolizes tamoxifen was assumed to be associated with the specific variant of the gene that an individual possesses, on the basis of studies that were conducted in breast cancer patients taking selective serotonin reuptake inhibitors (SSRIs) to relieve hot flashes. [3, 4, 5]

Specifically, because SSRIs inhibit CYP2D6, significantly lower endoxifen concentrations were also found in the studies’ patients. Further analysis identified 3 different groups of patients on the basis of genetic variants of CYP2D6: patients with 2 wild-type (wt), or normal, alleles; those with 1 non-wt allele; and those with 2 non-wt alleles. In a direct dose-gene effect, patients with 2 non-wt alleles had lower concentrations of endoxifen than did those with 1 non-wt allele, and patients with 2 wt alleles had endoxifen levels similar to those of poor metabolizers of tamoxifen who were not taking SSRIs. [4, 5]  Follow-up studies identified the *4 variant (1846G>A) as the most common allele associated with poor metabolism of tamoxifen. [6, 7]

A retrospective study conducted by Goetz et al showed that patients with the CYP2D6*4/*4 genotype had significantly shorter relapse-free time (RFT) and disease-free survival (DFS) time than did patients with *4/wt and wt/wt variants, although no difference was seen in overall survival. [6]  In addition, patients who were poor metabolizers, defined as those with *4/*4 alleles or patients on strong CYP2D6 inhibitors for 2-3 years, had significantly shorter time to recurrence, significantly worse RFT, and significantly higher risk of relapse than did patients with wt alleles and those not on CYP2D6 inhibitors. [8]

Results from a study of patients enrolled in a Stockholm Breast Cancer Group clinical trial showed that tamoxifen-treated patients with at least 1 CYP2D6*4 allele had a significantly better survival time than did those without the genetic variant. [9]

The polymorphism has more than 100 known alleles, and based on genotype combinations, these are commonly classified into 4 phenotypes [10] :

  • Ultra-rapid metabolizers (UM)
  • Extensive (normal) metabolizers (EM)
  • Intermediate metabolizers (IM)
  • Poor metabolizers (PM) 

Prediction of an impaired tamoxifen metabolizer phenotype (IM, PM) with low endoxifen formation capacity is potentially important for personalized treatment decisions in breast cancer, such as increasing the therapeutic dose or replacing tamoxifen with an AI. [11]

For more information, see Breast Cancer.

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Clinical Implications of CYP2D6 Variants

Among the most influential studies of the association between CYP2D6 genotype and tamoxifen effectiveness are the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98 trials, which together randomized more than 9000 patients to tamoxifen or to anastrozole or letrozole, respectively. [12, 13]

In both assessments, CYP2D6 allele status had no effect on any outcomes, including disease recurrence, distant recurrence, and overall survival. [14, 15] In addition, because it was thought that the presence of hot flashes might be an indicator of metabolic activity of tamoxifen, BIG 1-98 investigators also looked at whether the presence or absence of hot flashes might correlate with CYP2D6 allele status. Again, no difference was seen between the groups. [15]

Nevertheless, the question of whether CYP2D6 allele status influences outcomes from tamoxifen still remains. Critics of these assessments have challenged the inconsistent use of somatic versus germline DNA in testing for genetic mutations and possible deviations from accepted statistical methodology. [16] Indeed, a matched case-control study using data from the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that corrected for these factors found significant differences in disease recurrence in patients taking tamoxifen for 5 years, although the difference was not apparent in patients taking only 2-3 years of tamoxifen who were then switched to anastrozole. [8]

It has been suggested that the current data may be suspect because of poor understanding of the metabolism of tamoxifen and endoxifen within the cytochrome P450 pathway. [16]

Ongoing studies of patients with metastatic breast cancer that are incorporating genetic testing will add more information to the debate, [17] but it is unclear whether they will fully resolve the question of how and whether CYP2D6 allele status influences outcomes from tamoxifen therapy given in the adjuvant setting.

The International Tamoxifen Pharmacogenomics Consortium (ITPC) is currently compiling comprehensive information on CYP2D6 and other genetic variants associated with metabolism and effects of tamoxifen in women treated with tamoxifen for breast cancer. [18, 19, 20, 21]

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Guidelines

Currently, the National Comprehensive Cancer Network (NCCN) does not recommend testing for CYP2D6 variants in patients considering tamoxifen in the adjuvant setting, which matches the recommendation from the American Society of Clinical Oncology (ASCO) about not testing for CYP2D6 variants in patients considering tamoxifen as a breast cancer risk reduction strategy. [2, 22]  

There is evidence that SSRIs paroxetine and fluoxetine interfere with the enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular isoform of CYP2D6. The NCCN guidelines recommend that medications that have minimal or no impact on plasma levels of endoxifen should be substituted whenever possible. [2] These alternatives include ciitaloprom, venlafaxine and escitalopram. [23]

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